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INDE 216: Muscle Darren Salmi, MD Clinical Assistant Professor Department of Surgery (Division of Clinical Anatomy) Department of Pathology INDE 216 / FALL 2015 / Muscle Three main types of muscle 3ssue SKELETAL CARDIAC Striated morphology INDE 216 / FALL 2015 / Muscle Involuntary func6on SMOOTH Skeletal Muscle Longitudinal secPon •  Strong, quick contracPons •  Voluntary (contracPon depends on motor neuron input à to be covered in lab) Cross secPon INDE 216 / FALL 2015 / Muscle •  Muscle fiber = muscle cell •  Myofibril = bundles of contracPle proteins within each fiber •  Sarcoplasm = cytoplasm •  Sarcolemma = plasma membrane –  T tubule = indentaPon of sarcolemma carrying acPon potenPal and extracellular ions deep into cell •  Sarcoplasmic re3culum = smooth ER for calcium release –  Terminal cisternae = part of sarcoplasmic rePculum that flanks T tubule Skeletal Muscle Terminology INDE 216 / FALL 2015 / Muscle Skeletal Muscle •  In general there are two (and ½) kinds of muscle fibers: “slow” and “fast” (aka “red” and “white”) •  Most muscles are a mix of both types of fiber, though different muscles have different raPos “One Slow Red Ox” “Dark meat” has more myoglobin in it than “white meat” INDE 216 / FALL 2015 / Muscle (mnemonic for fiber types) Skeletal Muscle RelaPvely more type I RelaPvely equal type I&II RelaPvely more type II Furthermore, fiber type raPos vary from person to person INDE 216 / FALL 2015 / Muscle Certain Muscle CondiPons Affect Different Fiber Types Normal: type 1 & type 2 fibers are roughly the same size Atrophy: type 2 fibers are much smaller than type 1 fibers [In this stain, type 1 fibers are light, type 2 fibers are dark] INDE 216 / FALL 2015 / Muscle Let’s Look Inside a Muscle Fiber INDE 216 / FALL 2015 / Muscle AcPon potenPals carried by the T-­‐tubules trigger release of Ca2+ stores from the sarcoplasmic rePculum to the sarcoplasm, leading to contrac6on AcPon potenPal Ca2+ Ca2+ Ca2+ INDE 216 / FALL 2015 / Muscle AcPon potenPals carried by the T-­‐tubules trigger release of Ca2+ stores from the sarcoplasmic rePculum to the sarcoplasm, leading to contrac6on AcPon potenPal 2+
2+
Ca2+ Ca Ca INDE 216 / FALL 2015 / Muscle Muscle Fiber Organiza3on Muscle fiber Myofibrils Thick filaments (myosin) A band = area of thick filaments H band = area of thick filaments without overlapping thin filaments (center of A band) I band = thin filaments without overlapping thick filaments Z line = center of the I band where thin filaments acach to each other M line = the center of the A band where thick filaments acach to each other INDE 216 / FALL 2015 / Muscle Thin filaments (acPn) The funcPonal units of myofibrils are sarcomeres, the region between adjacent Z lines INDE 216 / FALL 2015 / Muscle Muscle contrac-on = sarcomere shortening INDE 216 / FALL 2015 / Muscle The Machinery of Contrac3on In relaxed muscle, myosin-­‐binding sites on acPn are blocked by tropomyosin Binding of calcium to troponin causes tropomyosin to move out of the way, allowing myosin to bind acPn INDE 216 / FALL 2015 / Muscle Muscle Contrac3on Myosin head -­‐Myosin head with ADP + Pi acaches to exposed binding site on acPn -­‐ADP + Pi is released and the myosin head pulls the acPn filament -­‐ATP acaches and the cycle repeats http://www.sci.sdsu.edu/movies/actin_myosin_gif.html INDE 216 / FALL 2015 / Muscle Muscle Contrac3on hcps://s-­‐media-­‐cache-­‐ak0.pinimg.com/originals/45/23/16/45231689e9252f7384b62fc8973ce3a1.jpg INDE 216 / FALL 2015 / Muscle Summary (words) 1-­‐ DepolarizaPon spreads across sarcolemma and into T-­‐tubules 2-­‐ Sarcoplasmic rePculum releases calcium into sarcoplasm 3-­‐ Calcium binds troponin, which shims tropomyosin and allows myosin heads to bind acPn 4-­‐ Myosin with acached ADP and Pi bind to acPn 5-­‐ Release of ADP and Pi from the myosin head causes it to bend 6-­‐ This bend pulls acPn inward, and thus the sarcomere shortens 7-­‐ New ATP binds to myosin head (which ATPase hydrolyzes to ADP and Pi) , and the myosin heads to cock back to its original posiPon 8-­‐ Cycle repeats as long as calcium (and ATP) is sPll present, causing further shortening of the sarcomere INDE 216 / FALL 2015 / Muscle Summary (video) hcp://www.sumanasinc.com/webcontent/animaPons/content/muscle.html INDE 216 / FALL 2015 / Muscle Muscular Dystrophies •  Group of disorders caused by defecPve connecPons between sarcomere and sarcolemma/ECM •  Dystrophin molecule is huge (>3500 amino acids, 79 exons over 2.6 Mbp, takes 16 hours to transcribe!) •  Progressive degeneraPon of muscle fibers is apparently due to mechanical damage caused by contracPons in the absence of adequate anchoring to supporPng structures INDE 216 / FALL 2015 / Muscle Duchenne Muscular Dystrophy •  X linked, affects 1:3500 boys •  Progressive skeletal muscle wasPng, omen wheelchair-­‐
bound by ~10 years old •  Progressive breathing difficulty due to wasPng of diaphragm muscle •  Life expectancy = late 20s-­‐
early 30s INDE 216 / FALL 2015 / Muscle DMD DMD •  Muscle biopsy shows dying fibers with inflammaPon •  Some regeneraPve fibers can be seen •  Immunohistochemical staining shows an absence of the protein dystrophin Normal: dystrophin stain + Macrophages phago-­‐
cytosing dead fibers DMD: dystrophin stain -­‐ RegeneraPng fiber with a central nucleus INDE 216 / FALL 2015 / Muscle Skeletal Muscle Regenera3on satellite cell •  Amer muscle damage, special skeletal muscle stem cells called satellite cells proliferate into myoblasts which fuse to form a new muscle fiber INDE 216 / FALL 2015 / Muscle Myosta3n •  Mature skeletal muscle fibers secrete myostaPn, which suppresses satellite cell acPvaPon •  Therefore, damage to a fiber leads to reduced myostaPn and increased regeneraPon •  Racing dogs homozygous for myostaPn deficiency are significantly more muscular •  MyostaPn inhibitors may help to slow progression of muscular dystrophies INDE 216 / FALL 2015 / Muscle Cardiac Muscle •  Microanatomy of cardiac muscle is very similar to skeletal muscle (T-­‐tubules, myofibrils, etc.) •  There are more differences at the Pssue level (morphology, conducPon, etc. will be covered in lab later this amernoon) •  Also, cardiac muscle cells don’t regenerate like skeletal muscle. We will talk about what does happen to damaged cardiac cells in “Injury/Repair” INDE 216 / FALL 2015 / Muscle Smooth Muscle •  Long, thin, spindle-­‐shaped cells with a single central nucleus •  Compared to striated muscle, smooth muscle produces slow, steady contracPons Cross secPon Longitudinal secPon Elongated cells with a single central nucleus INDE 216 / FALL 2015 / Muscle Smooth Muscle Filaments •  Smooth muscle cells have thick and thin filaments, but they are not arranged in the orderly fashion of striated muscle, instead they crisscross the cell •  AcPn-­‐myosin complexes are acached to each other at dense bodies (aka focal densi3es) which are analogous to Z-­‐lines of striated muscle INDE 216 / FALL 2015 / Muscle Smooth Muscle Contrac3on •  ContracPon is dependent on calcium release from sarcoplasmic rePculum •  However, Ca2+ binds calmodulin, which acPvates myosin light-­‐
chain kinase, which phosphorylates myosin and permits binding to acPn •  The rest is similar to striated muscle INDE 216 / FALL 2015 / Muscle Smooth Muscle •  Smooth muscle is widely distributed throughout the body –  Organs: peristalsis of GI tract –  Dermis: arrector pili muscle –  Blood vessels: blood pressure regulaPon INDE 216 / FALL 2015 / Muscle Control of Smooth Muscle Contrac3on •  Smooth muscle contracPons are controlled by a wide variety of involuntary mechanisms including: –  Autonomic nerves –  Local metabolites –  Hormones –  Temperature INDE 216 / FALL 2015 / Muscle Summary -­‐ Muscle •  3 types of muscle: skeletal, cardiac, smooth •  Difference between type 1 & 2 skeletal muscle fibers •  Microanatomy of a muscle fiber –  T-­‐tubules –  Sarcoplasmic rePculum –  Myosin and acPn •  How muscle Pssue contracts –  Skeletal: Ca2+ + troponin à tropomyosin uncovers binding site, ATP-­‐dependent movement of myosin head against acPn shortens sarcomere –  Cardiac: similar –  Smooth: similar, but Ca2+ + calmodulin à myosin light-­‐chain kinase phosphorylaPon uncovers binding site •  Smooth muscle features –  Similar microanatomy, but less parallel and more crisscross arrangement of myosin-­‐acPn –  Variety of involuntary mechanisms INDE 216 / FALL 2015 / Muscle